Tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD and its metabolites in monkey lung transplant recipients: Interaction with cyclosporine

We report the tissue distribution and clinical monitoring of the novel macr olide immunosuppressant SDZ-RAD [40-O-(2-hydroxyethyl)-rapamycin] and its m etabolites in monkey lung transplant recipients as well as its interaction with cyclosporine as the Neoral formulation. After left unilateral lung tra nsplantation, cynomolgus monkeys received by oral administration either 1) 1.5 mg/kg/day SDZ-RAD (n = 4); 2) 100 mg/kg/day cyclosporine (n = 4); 3) 0. 3 mg/kg/day SDZ-RAD + 100 mg/kg/day cyclosporine (n = 6); 4) 1.5 mg/kg/day SDZ-RAD + 50 mg/kg/day cyclosporine (n = 5); or 5) SDZ-RAD and cyclosporine doses adjusted according to trough blood concentration measurements (n 5 6 ). At the end of the observation period (usually 29 days after transplantat ion), and 24 h after the last doses, tissue samples were collected and anal yzed with HPLC/mass spectrometry. Gall bladder, pancreas, the transplant lu ng, cerebellum, kidneys, and spleen had the highest SDZ-RAD concentrations. Coadministration of cyclosporine increased SDZ-RAD concentrations in most tissues as well as tissue-to-blood distribution coefficients. In contrast, SDZ-RAD had only a small effect on cyclosporine blood and tissue concentrat ions. Rejection in lung grafts in monkeys treated with either of the cyclos porine/SDZ-RAD combinations was significantly less than in the monotherapy groups (P < .002). Histological rejection scores were inversely correlated with SDZ-RAD concentrations in blood (r = -0.58; P < .001; n = 24), lymph n odes (P = -0.58; P < .003; n = 24), thymus (r = -0.63; P < .001; n = 23) an d transplant lung tissue (r = -0.58; P < .003; n = 24). We conclude that, i n addition to the synergistic pharmacodynamic interaction, a pharmacokineti c interaction resulting in higher SDZ-RAD tissue concentrations contributed to the significantly better immunosuppressive efficacy when both drugs wer e combined compared with monotherapy.